journal contribution
posted on 2023-03-31, 20:03 authored by Dong Woo Kang, Bo Hui Lee, Young-Ah Suh, Yong-Seok Choi, Se Jin Jang, Yong Man Kim, Kang-Yell Choi, Do Sik Min <p>Figure S1 Depletion of PLD1 downregulates Wnt/β-catenin signaling via upregulation of ICAT; Figure S2 PI3K/Akt-E2F1 signaling pathways are involved in PLD1 inhibition-induced ICAT upregulation; Figure S3 PLD1-PI3K/Akt-TopBP1-E2F1 signaling pathways are involved in the regulation of ICAT expression and β-catenin/TCF transactivation; Figure S4 Immunoactivity of p-Akt, ICAT and PLD1 in PLD1 inhibitortreated PDX models; Table S1 CRC patients' clinical characteristics for primary cell culture; Table S2. Factors of multivariates variables, gender, age, organ, tumor stage, and the protein pairs using Cox's proportional hazards model.</p>
Funding
National Research Foundation of Korea (NRF) grants
Translational Research Center for Protein Function Control Grant
History
ARTICLE ABSTRACT
Purpose: Dysregulated expression of PLD1 has emerged as a hallmark feature of colorectal cancer, which remains a major cause of mortality worldwide. Aberrant activation of Wnt/β-catenin signaling is a critical event in the development of colorectal cancer. Here, we investigated molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways via inhibitor of β-catenin and T-cell factor (ICAT), a negative regulator of Wnt/β-catenin signaling. We also explored the effect of PLD1 inhibition on growth of colorectal cancer hyperactivated by Wnt/β-catenin and PI3K/Akt signaling.Experimental Design: Expression of ICAT via targeting of PLD1 was assessed in vivo in ApcMin/+ mice, an AOM/DSS model, and in vitro using various colorectal cancer cells. The relationship between ICAT/PLD1 expression and prognostic survival value of 153 colorectal cancer patients was examined. The therapeutic efficacy of PLD1 inhibitor was determined using a patient-derived xenograft model carrying APC and PI3K mutations.Results: PLD1 promoted the Wnt/β-catenin signaling pathway by selectively downregulating ICAT via the PI3K/Akt-TopBP1-E2F1 signaling pathways. Low PLD1 expression and high ICAT expression were significantly associated with increased survival in colorectal cancer patients and vice versa. Furthermore, PLD1 inhibition suppressed growth of colorectal cancer activated by the Wnt/β-catenin and PI3K signaling pathways.Conclusions: These results suggest that PLD1 linked to ICAT mediates molecular crosstalk between the Wnt/β-catenin and PI3K/Akt pathways and thus could be proposed as a novel colorectal cancer prognostic biomarker. These results may assist in the clinical development of a PLD1 inhibitor for treatment of colorectal cancer patients carrying APC and PI3KCA mutations. PLD1, a nodal modifier, acts as a potential therapeutic target for the treatment of colorectal cancer hyperactivated by the Wnt/β-catenin and PI3K/Akt signaling pathways. Clin Cancer Res; 23(23); 7340–50. ©2017 AACR.
